Behavioral and Neural Plasticity in the Aged As a general hypothesis, we propose that age-related accumulation of aberrant forms of A?, including various soluble assembly states, as well as fibrillar deposits in the parenchyma and vessels activate innate immune responses, which induce a low level chronic cascade of proinflammatory cytokines and chemokine. The combination of elevated levels of pathological forms of A? and chronic inflammation disrupts trophic factor signaling and cerebrovascular function, and directly contributes to neurodegeneration. We will use novel transgenic model systems and specifically for the 3xTg-AD model which is marked by both AB and tau pathology, generate various crosses and draw comparisons to pathology and mechanisms in human control and AD brain tissues. To address this larger goal, we have assembled a team of investigators with expertise in A?, inflammation and brain pathology and who have a history of working together: Dr. C. Glabe who will investigate A?, A? oligomers and assembly states using conformation specific antibodies in transgenic models and human brain tissues. Dr. C. Cotman will examine the effects of A? assemblies on signal transduction mechanisms and AD pathology. Dr. F. LaFerla, who brings expertise on the development and characterization of novel transgenic model systems, will investigate the role A? and inflammation on the evolution of tau pathology. Dr. A. Tenner will investigate the role of complement on AD pathology and the balance between protective and detrimental effects on the brain and AD. Dr Cribbs will use transgenic models and brain tissues to investigate the mechanism for the development of vascular pathology and along with other program investigators determine how vascular pathology interacts with non-vascular pathology. The efforts of the team will be supported by an Administrative Core (Core A) and a Tissue and Peptide resources Core (Core B). Core B will generate A?, antibodies, assist in the maintenance of transgenic lines and provide well-characterized human brain tissues.